Our overall goal is to characterize and understand the events that occur in the human central nervous system in response to menopause. We have found that human menopause is characterized by a striking hypertrophy of neurons within the hypothalamic infundibular nucleus. Postmenopausal neuronal hypertrophy occurs in a subpopulation of neurons containing estrogen receptor and neurokinin B (NKB) mRNA and is accompanied by a marked increase in tachykinin gene expression. GnRH gene expression also increases, but in a separate subpopulation of hypothalamic neurons. During our last funding period, we used animal models to provide strong evidence that the changes in NKB cell size and gene expression in postmenopausal women are due to removal of steroid negative feedback. In this renewal, we propose the first studies to elucidate the physiological relevance of the increase in NKB gene expression in postmenopausal women. In specific aim 1, we will test the hypothesis that NKB neurons participate in the hypothalamic circuitry regulating LH secretion in the rat using pharmacological tools and antisense oligodeoxynucleotide (ODN) knockdown techniques. In specific aim 2, we will characterize the anatomic relationship between arcuate NKB neurons and the reproductive axis. We will determine if arcuate NKB or NK3 receptor-immunoreactive neurons project to the preoptic-septal region (site of GnRH neurons) or the primary capillary plexus of the median eminence in the rat. We will also determine if GnRH neurons express NK3 receptor-immunoreactivity in the human or rat hypothalamus. In specific aim 3, we will attempt to gain a deeper understanding of the remarkable changes in the infundibular nucleus of postmenopausal women. We will determine if menopause is association with signs of cellular degeneration such as increased microglial cells or GFAP gene expression. We will also use the Golgi-method to determine if the neuronal hypertrophy is associated with expansion or regression of infundibular dendritic arbors. Our studies provide an exceptional opportunity to study human brain specimens and address basic biological, issues directly relevant to the physiology of postmenopausal women.